RSK2 signals through stathmin to promote microtubule dynamics and tumor metastasis

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Abstract

Metastasis is responsible for >90% of cancer-related deaths. Complex signaling in cancer cells orchestrates the progression from a primary to a metastatic cancer. However, the mechanisms of these cellular changes remain elusive. We previously demonstrated that p90 ribosomal S6 kinase 2 (RSK2) promotes tumor metastasis. Here we investigated the role of RSK2 in the regulation of microtubule dynamics and its potential implication in cancer cell invasion and tumor metastasis. Stable knockdown of RSK2 disrupted microtubule stability and decreased phosphorylation of stathmin, a microtubule-destabilizing protein, at serine 16 in metastatic human cancer cells. We found that RSK2 directly binds and phosphorylates stathmin at the leading edge of cancer cells. Phosphorylation of stathmin by RSK2 reduced stathmin-mediated microtubule depolymerization. Moreover, overexpression of phospho-mimetic mutant stathmin S16D significantly rescued the decreased invasive and metastatic potential mediated by RSK2 knockdown in vitro and in vivo. Furthermore, stathmin phosphorylation positively correlated with RSK2 expression and metastatic cancer progression in primary patient tumor samples. Our finding demonstrates that RSK2 directly phosphorylates stathmin and regulates microtubule polymerization to provide a pro-invasive and pro-metastatic advantage to cancer cells. Therefore, the RSK2–stathmin pathway represents a promising therapeutic target and a prognostic marker for metastatic human cancers.

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Acknowledgements

We acknowledge Dr Anthea Hammond for editorial assistance. We thank the shared resources facilities of the Winship Cancer Institute and the Integrated Cellular Imaging Core of Emory University. We also acknowledge and thank Dr Shi-Yong Sun for his insightful scientific input in the development of this work. This work was supported in part by NIH grants R01 CA175316 (to SK), F31 CA183365 (to GNA) and ACS grant RSG-11-081-01 (to SK). GNA is an NIH predoctoral fellow. FRK and SK are Georgia Cancer Coalition Scholars. SK is a Robbins Scholar and an American Cancer Society Basic Research Scholar.

Author contributions

YK, ZGC, DMS and FRK provided critical reagents. LJ performed IHC staining and BLI study. KRM performed histopathological study. GNA and DL performed all the other experiments. GNA, LJ and SK designed the study and wrote the manuscript.

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Correspondence to S Kang.

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The authors declare no conflict of interest.

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Alesi, G., Jin, L., Li, D. et al. RSK2 signals through stathmin to promote microtubule dynamics and tumor metastasis. Oncogene 35, 5412–5421 (2016). https://doi.org/10.1038/onc.2016.79

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